Metaxalone, 5-[(3,5-dimethylphenoxy)methyl]-2-oxazolidinone, shown below, is a musclerelaxant used to relax muscles and relieve pain caused by strains, sprains, and other musculoskeletal conditions, particularly muscle spasms and back pain.
Metaxalone is a white to almost white, odourless crystalline powder freely soluble in chloroform, soluble in methanol and in 96% ethanol but practically insoluble in water. Metaxalone melts, without decomposition, at 121.5-123° C. Metaxalone is further described at Monograph no. 5838 of the Merck Index (Eleventh Addition, Merck & Co., 1989) and is also identified by CAS Registry Number: 1665-48-1. Preparation of metaxalone is described in Lunsford et al., J. Am. Chem. Soc. 82, 1166 (1960) and U.S. Pat. No. 3,062,827.
Metaxalone is marketed in 800 mg tablets under the SKELAXIN® tradename. As an interneuronal blocking agent, metaxalone acts on the central nervous systems (CNS) to produce muscle relaxant effects, and is used as an adjunct to rest, physical therapy, and other measures for the relief of discomforts associated with painful musculoskeletal conditions. Metaxalone is used to treat acute, painful muscle spasms. The mechanism of action of metaxalone in humans has not been established but may be due to general central nervous system depression. Metaxalone has no direct action on the contractile mechanism of striated muscle, the motor end plate, or the nerve fiber. The bioavailability of metaxalone is significantly improved when it is taken with food. Specifically, in one study, compared to fasted conditions, the presence of food at the time of drug administration increased C(max) by 177.5% and increased AUC(last) by 123.5% and AUC(inf) by 115.4%. Based on the information in the SKELAXIN® product data sheet, patients receiving metaxalone therapy are informed that, due to a food effect, taking metaxalone with food may result in an increase in the oral bioavailability of metaxalone compared to taking metaxalone without food. See SKELAXIN® Product Data Sheet, April 2008; U.S. Pat. Nos. 6,407,128; and 6,683,102; and http://en.wikipedia.org/wiki/Metaxalone, Dec. 6, 2009. This food effect may effect dosing for a particular patient. In view of the food effect on metaxalone bioavailabity, the currently developed formulations of metaxalone do not achieve the goal of a sufficiently bioavailable form of metaxalone.
Active pharmaceutical ingredients (API's) which, like metaxalone, are generally less water soluble and less bioavailable create huge problems for the pharmaceutical industry. Research has shown that some drug candidates fail in the clinical phase due to poor human bioavailability and problems with the formulation. Traditional methods to address these problems, without completely redesigning the molecule, include salt selection, producing amorphous material, particle size reduction, pro-drugs, and different formulation approaches. Some attempts to use such techniques with metaxalone are described, for example, in WO 2004/019937 A1, WO 2005/016310 A1, WO 2007/079189 A2, and WO 2009/19662 A2.
Although therapeutic efficacy is the primary concern for an API, the salt and solid state form (i.e., the crystalline or amorphous form) of a drug candidate can be critical to its pharmacological properties and to its development as a viable API. Recently, crystalline forms of API's have been used to alter the physicochemical properties of a particular API. Each crystalline form of a drug candidate can have different solid state (physical and chemical) properties. The differences in physical properties exhibited by a novel solid form of an API (such as a cocrystal or polymorph of the original therapeutic compound) affect pharmaceutical parameters such as storage stability, compressibility and density (important in formulation and product manufacturing), and solubility and dissolution rates (important factors in determining bioavailability). Because these practical physical properties are influenced by the solid state properties of the crystalline form of the API, they can significantly impact the selection of a compound as an API, the ultimate pharmaceutical dosage form, the optimization of manufacturing processes, and absorption in the body. Moreover, finding the most adequate solid state form for further drug development can reduce the time and the cost of that development.
Obtaining crystalline forms of an API is extremely useful in drug development. It permits better characterization of the drug candidate's chemical and physical properties. It is also possible to achieve desired properties of a particular API by forming a cocrystal of the API and a coformer. Crystalline forms often have better chemical and physical properties than the free base in its amorphous state. Such crystalline forms may, as with the cocrystals of the invention, possess more favorable pharmaceutical and pharmacological properties or be easier to process than known forms of the API itself. For example, a cocrystal may have different dissolution and solubility properties than the API itself and can be used to deliver APIs therapeutically. New drug formulations comprising cocrystals of a given API may have superior properties over its existing drug formulations. They may also have better storage stability.
Another potentially important solid state property of an API is its dissolution rate in aqueous fluid. The rate of dissolution of an active ingredient in a patient's stomach fluid may have therapeutic consequences since it impacts the rate at which an orally administered active ingredient may reach the patient's bloodstream.
A cocrystal of an API is a distinct chemical composition of the API and coformer and generally possesses distinct crystallographic and spectroscopic properties when compared to those of the API and coformer individually. Crystallographic and spectroscopic properties of crystalline forms are typically measured by X-ray powder diffraction (XRPD) and single crystal X-ray crystallography, among other techniques. Cocrystals often also exhibit distinct thermal behavior. Thermal behavior is measured in the laboratory by such techniques as capillary melting point, thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC).